Ceruloplasmin contains the majority of the copper in plasma or serum in humans and animals. Ceruloplasmin levels are markedly increased in pregnancy and cancer, with smaller increases occurring in some other disease states. We have recently demonstrated that this glycoprotein is the main source of copper for normal malignant cells. Turnover of ceruloplasmin copper is rapid, especially in rats with implanted tumors, and substantial amounts of copper accumulate in tumors. Since certain forms of copper chelates are known to inhibit tumor growth, the question arises whether ceruloplasmin, or the other forms of serum copper, play a role in host defense or, conversely, promote cell proliferation. Uptake of ceruloplasmin copper occurs by two different mechanisms, one involving removal of copper, the other uptake of the whole ceruloplasmin molecule. The nonceruloplasmin portion of serum copper is mainly on albumin but also is present as small molecular weight material. The albumin fraction does serve as a source of copper, especially for liver and kidney, but is quantitatively not as important as ceruloplasmin. The small molecular weight fraction has not been studied in this regard but may contain growth modulating and angiogenesis-promoting factors. We propose to study the mechanisms of uptake of ceruloplasmin copper in normal and tumor cells, with a view to identifying, characterizing and isolating specific membrane receptors and studying their number in relation to the rates of copper uptake and cell growth. We also will investigate the chemical nature and physiological effects of the small molecular weight serum copper fraction, and determine whether there are variations in the size of this pool in cancer and other states.